Examining hypothalamic-pituitary-adrenal axis genetic variation on cortisol and alpha-amylase reactivity during an explicit negative-evaluative stress induction.

Prior work consistently links additive genetic variation in the hypothalamic-pituitary-adrenal (HPA) axis-a multilocus genetic profile score (MGPS)-to depression risk in the context of stress exposure. However, despite that HPA MGPS variants were selected based on evidence that they elevate cortisol reactivity, there are surprisingly few tests of whether an HPA MGPS elevates cortisol reactivity to lab-based stress. Similarly, despite neurobiological connections and coordination between the HPA axis and the sympathetic nervous system (e.g., in the paraventricular nucleus and locus coeruleus), no work has tested whether an HPA MGPS influences sympathetic nervous system reactivity to stress. We investigated whether an HPA MGPS moderates the relation between lab-based stress and: (1) HPA activity indexed by cortisol, and/or (2) sympathetic activity indexed by salivary alpha-amylase, sAA. Emerging adults (N = 152; mean age = 19.5, largest subsample 44.4% Black/African American) were randomly assigned to one of two Trier Social Stress Test variations, a non-evaluative control, or an explicitly negative-evaluative condition. Participants provided DNA and repeated saliva samples for sAA and cortisol. The HPA MGPS did not significantly moderate the relationship between stress condition and cortisol or sAA reactivity, respectively; moreover, post-hoc tests highlight that individual polymorphisms showed non-significant effects in opposite directions from each other, cancelling out in aggregate. Findings suggest that the HPA MGPS's associations with cortisol reactivity are not as straightforward as initially believed. We speculate that the relationships of some HPA variants to biomarker reactivity may vary between modest lab-based stressors and the explicit negative-evaluative induction used here.

Relative Age Effect and ACTN3 R577X and ACE I/D Polymorphisms in Brazilian Football Players: An Association Genetic Study.

The Relative Age Effect (RAE) suggests older athletes within an annual cohort have advantages over their younger peers. We hypothesized that younger athletes could overcome these disadvantages through favorable α-actinin-3 (ACTN3) and angiotensin converting enzyme (ACE) polymorphisms. This study aimed to: 1) examine RAE prevalence among Brazilian football players; 2) investigate the distribution of the ACTN3 and ACE polymorphisms; and 3) explore the association between polymorphisms and RAE across competitive levels and positions. The sample included 627 male players from first-division Brazilian teams in four age categories: U15 (n = 172), U17 (n = 166), U20 (n = 161), and Professionals (n = 128). A control group was established using data from the general Brazilian population documented in previous studies Results showed RAE presence across all competitive levels and positions. Players with the ACTN3 R allele, especially the RR genotype, had the strongest associations with football players, particularly among defenders. On the other hand, the distribution of ACE polymorphism was not significantly different between controls and players, except in the U17 category, where the I/I genotype was more common. Relatively older players had higher total genotype scores than younger counterparts in the overall sample and defender subgroups. In conclusion, RAE is prevalent among Brazilian football players, with older athletes benefiting from favorable ACTN3 and ACE polymorphisms, contrary to our initial hypothesis.

Biochar amendment affects the microbial genetic profile of the soil, its community structure and phospholipid fatty acid contents.

Biochar (BC) amendment has been proposed as a promising strategy for mitigating greenhouse gas (GHG) emissions, specifically carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O). Conducting a meta-analysis to evaluate the impact of biochar on microbial genetic profile, community structure, and phospholipid fatty acid (PLFA) contents can aid in identifying key microbial groups involved in GHG production and consumption, and assessing the overall effectiveness of biochar in reducing GHG emissions. The present meta-analysis revealed that the addition of biochar resulted in a 22 % and 41 % reduction in pmoA and mcrA genes of methanogenic microorganisms, respectively. The mcrA/pmoA ratio significantly increased by 81 %. Gene abundances exhibited a positive response to biochar amendment, with increases observed in nifH, nirK, nirS, nosZ, and nosZ (nirS + nirK) genes by 13 %, 32 %, 37 %, 42 %, and 79 %, respectively. Moreover, biochar amendment influenced the microbial community structure accordingly. The concentration of PLFAs increased in response to BC treatment in the following order: A-bacteria (+49 %) < Fungi (+30 %) < Gram-pb (+21 %) < G-bacteria (+17 %) < Gram-nb (+11 %). These findings indicate that biochar amendment shapes the microbial community structure, further emphasizing its significance in enhancing soil fertility.

The Effects of Variation in the GABAA Receptor Gene on Anxious Depression are Mediated by the Functional Connectivity Between the Amygdala and Middle Frontal Gyrus.

Background: γ-aminobutyric acid (GABA) and its main receptor, the GABAA receptor, are implicated in major depressive disorder (MDD). Anxious depression (AD) is deemed to be a primary subtype of MDD. The amygdala and the dorsolateral prefrontal cortex (DLPFC) are key brain regions involved in emotional regulation. These regions contain the most GABAA receptors. Although the GABAergic deficit hypothesis of MDD is generally accepted, few studies have demonstrated how GABAA receptor gene polymorphisms affect the functions of specific brain regions, in particular, the amygdala and the DLPFC. Methods: The sample comprised 83 patients with AD, 70 patients with non-anxious depression (NAD), and 62 healthy controls (HC). All participants underwent genotyping for polymorphisms of GABAA receptor subunit genes, followed by a resting-state fMRI scan. The HAMD-17 was used to evaluate the severity of MDD. ANOVA was performed to obtain the difference in the imaging data, GABAA receptor multi-locus genetic profile scores (MGPS), and HAMD-17 scores among three groups, then the significant differences between AD and NAD groups were identified. Mediating effect analysis was used to explore the role of functional connectivity (FC) between the amygdala and DLPFC in the association between the GABAA receptor gene MGPS and AD clinical features. Results: Compared with the NAD group, the AD group had a higher GABAA receptor MGPS. AD patients exhibited a negative correlation between the MGPS and FC of the right centromedial (CM) subregion, and the right middle frontal gyrus (MFG). A negative correlation was also observed between the MGPS and anxiety/somatic symptoms. More importantly, the right CM and right MFG connectivity mediated the association between the GABAA receptor MGPS and anxiety/somatic symptoms in patients with AD. Conclusion: The decreased FC between the right MFG and right CM subregion mediates the association between GABAA receptor MGPS and AD.

Clinical and genetic profile of Chinese patients with indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract.

Indolent natural killer cell lymphoproliferative disorder of the gastrointestinal tract (iNKLPD-GI) is an uncommon, recently recognized lymphoid proliferation of mature NK cells primarily manifesting in the GI tract. Unlike NK/T lymphoma, iNKLPD-GI exhibits a rather indolent clinical course, underscoring the need for cautious management to prevent unnecessary interventions. However, clinical and molecular features of this entity have not been thoroughly understood. This study aimed to add more information to the current knowledge of this disease. Seven patients with iNKLPD-GI were included in our study. Clinical data included initial symptoms, endoscopic manifestations, pathological features, and therapies. Besides, next-generation sequencing was arranged to explore the underlying genetic mechanism of this disease. In our study, iNKLPD-GI in the urinary bladder was first identified. Edema of extremities (3, 42.8 %) was the most prevalent onset symptom which was reported for the first time. Pathological and immunohistological features were found to display the phenotype of NK cells. Unlike extranodal NK/T cell lymphoma, Epstein-Barr virus-encoded small RNA (EBER) were negative in all patients. Moreover, we found that two patients harbored JAK3 mutation. Apart from JAK3 K563_C565del previously reported in the literature, we discovered new JAK3 mutation sites. Other mutations including BRAF, KRAS, and SH2B3 were also identified. In conclusion, iNKLPD-GI was an indolent atypical NK-cell proliferation with diverse clinical characteristics. "Watch and wait" therapy was preferable to intense chemotherapy. Recurrent JAK3 mutation may be the underlying mechanism responsible for the neoplastic nature of the disease and may serve as a potential target for patients with severe symptoms.

[Endometrial carcinoma: molecular classification in routine pathology]. / Endometriumkarzinom: molekulare Klassifikation in der Routinepathologie.

The molecular classification of endometrial carcinoma defines four main groups: polymerase­É›(PolE) gene mutated, microsatellite unstable (MSI), p53 abnormal tumors and tumors with no specific molecular profile (NSMP). This classification provides significant insights into the prognosis and therapeutic decisions. Each group exhibits unique genetic profiles identified through immunohistochemistry and molecular diagnostics, enabling personalized treatment. The identification of these molecular signatures necessitates precise analytical methods, selected based on the local circumstances at each site. The approach to molecular classification highlights the critical role of pathology in the diagnosis and emphasizes the necessity of collaboration between the clinic and pathology.

Polygene by environment interactions predicting depressive outcomes.

Depression is a major public health problem with a continued need to uncover its etiology. Current models of depression contend that gene-by-environment (G × E) interactions influence depression risk, and further, that depression is polygenic. Thus, recent models have emphasized two polygenic approaches: a hypothesis-driven multilocus genetic profile score (MGPS; "MGPS × E") and a polygenic risk score (PRS; "PRS × E") derived from genome-wide association studies (GWAS). This review for the first time synthesizes current knowledge on polygene by environment "P × E" interaction research predicting primarily depression-related outcomes, and in brief, neurobiological outcomes. The "environment" of focus in this project is stressful life events. It further discusses findings in the context of differential susceptibility and diathesis-stress theories-two major theories guiding G × E work. This synthesis indicates that, within the MGPS literature, polygenic scores based on the serotonin system, the HPA axis, or across multiple systems, interact with environmental stress exposure to predict outcomes at multiple levels of analyses and most consistently align with differential susceptibility theory. Depressive outcomes are the most studied, but neuroendocrine, and neuroimaging findings are observed as well. By contrast, vast methodological differences between GWAS-based PRS studies contribute to mixed findings that yield inconclusive results.

Genomic tools for early selection among Thoroughbreds and Polo Argentino horses for practicing polo.

The Polo Argentino (PA) horse is a recognized breed, developed originally by mixing crossbred and Thoroughbred (TB) horses to play polo. Early PA selection is difficult due to unreliable performance estimations. This study investigated the usefulness of genomic markers previously linked to morphological and functional traits as a tool for the early selection of PA. To this, we genotyped 520 PA and 30 TB horses using the Equine GGPArray (Illumina, n = 71,778 SNPs). Analyses included a genetic characterization of six genetic markers associated with behavioral (DRD4), muscular development (MSTN), and body size (LCORL, HMGA6, ZFAT, and LASP1) genes. Genetic differences in the DRD4, MSTN, and LCORL SNP were found between the two breeds, in the last two FST index between breeds was 0.13 and 0.6, respectively (p < 0.01). In DRD4, G allele was the more prevalent in PA (0.56 vs 0.45 in TB, p < 0.05), but no differences were observed between the genotypes associated with phenotypes. In MSTN, heterozygous genotypes were the most common in PA (48 %), with a significant decrease in AA (Hardy-Weinberg p < 0.05), suggesting a negative selection against it in polo horses. In body size, HMGA2 was monomorphic in all horses, while ZFAT and LASP1 SNP showed higher variability. Interestingly, 99 % of PA showed a TT genotype in LCORL (only 66 % in TB), demonstrating selection for smaller horses. Our results suggest that empirical selection in PA has generated an incipient genomic differentiation in discrete traits which could be used as a marker-assisted selection tool for early selection of polo horses.

Genetic analysis of cervical cancer with lymph node metastasis.

OBJECTIVE: To find out the differences in gene characteristics between cervical cancer patients with and without lymph node metastasis, and to provide reference for therapy. METHODS: From January 2018 to June 2022, recurrent cervical cancer patients 39 cases with lymph node metastasis and 73 cases without lymph node metastasis underwent testing of 1,021 cancer-related genes by next-generation sequencing. Maftools software was used to analyze somatic single nucleotide/insertion-deletion variation mutation, co-occurring mutation, cosmic mutation characteristics, oncogenic signaling pathways. RESULTS: EP300 and FBXW7 were significantly enriched in lymph node-positive patients. Lymph node-positive patients with EP300 or FBXW7 mutations had lower overall survival (OS) after recurrence. Both lymph node-positive and -negative patients had plenty of co-occurring mutations but few mutually exclusive mutations. Lymph node-positive co-occurring mutation number ≥6 had lower OS, while lymph node-negative co-occurring mutation number ≥3 had lower OS after recurrence. The etiology of SBS3 was defects in DNA double strand break repair by homologous recombination, which exclusively exist in lymph node-positive patients. There was no difference in median tumor mutation burden (TMB) between positive and negative lymph nodes, but TMB was significantly associated with PIK3CA mutation. CONCLUSION: The somatic SNV/Indels of EP300 and FBXW7, SBS3 homologous recombination-mediated DNA repair defect were enriched in lymph node-positive patients. For lymph node-positive patients, EP300 or FBXW7 mutations predicted poor prognosis. No matter lymph node-positive or negative, more co-occurring mutation number predicted poor prognosis. PIK3CA mutation may account for the higher TMB and help identify patients who benefit from immunotherapy.

Tracing the fine-scale demographic history and recent admixture in Hmong-Mien speakers.

The linguistic, historical, and subsistent uniqueness of Hmong-Mien (HM) speakers offers a wonderful opportunity to investigate how these factors impact the genetic structure. The genetic differentiation among HM speakers and their population history are not well characterized. Here, we generate genome-wide data from 65 Yao ethnicity samples and analyze them with published data, particularly by leveraging haplotype-based methods. We determined that the fine-scale genetic substructure of HM speakers corresponds better with linguistic classification than with geography. Particularly, parallels between serial founder events and language differentiations can be observed in West Hmongic speakers. Multiple lines of evidence indicate that ~500-year-old GaoHuaHua individuals are most closely related to West Hmongic-speaking Bunu. The strong genetic bottleneck of some HM-speaking groups, especially Bunu, could potentially be associated with their long-term practice of swidden agriculture to some degree. The inferred admixture dates for most of the HM speakers overlap with the reign of the Ming dynasty (1368-1644 CE). Besides a common genetic origin for HM speakers, their genetic ancestry is shared primarily with neighboring Han Chinese and Tai-Kadai speakers in south China. In conclusion, our analyses reveal that recent isolation and admixture events have contributed to the genetic population history of present-day HM speakers.

A Systematic Review of Epigenetics of Endometriosis.

Objective: To assess the current literature evaluating the epigenetics of endometriosis in humans. Evidence Review: A systematic review was conducted in accordance with the PRISMA guidelines within PubMed, EBSCOhost, Cochrane Library, Embase, Scopus, and Web of Science Core Collection. A comprehensive search strategy was developed by a data informationist. Observational and interventional studies assessing epigenetics in humans published in English up to January 15th, 2023, were included. Two reviewers independently screened studies evaluating the role of epigenetics in endometriosis. The risk of bias was assessed using Cochrane RoB 2.0 tool and the Newcastle-Ottawa scale. Extracted data were analyzed descriptively. Results: We identified 18.639 studies, of which 57 were included, comprising 1.623 patients with endometriosis and 1.243 controls. Among the 57 studies included, 50 (88%) were case-control studies, and 7 (12%) were cross-sectional. Fifty-nine percent of the studies were Asian, 25% were from America, 14% were European, and 2% were from Africa. Acetylation and methylation were the two main key histone modifications that were centered in this review. Accordingly, we classified the studies as those focusing on genome-wide methylation and those on histone acetylation. Several studies identified an association between endometriosis and hypermethylated genes, including the PGR-B, SF-1, and RASSF1A. The genes HOXA10, COX-2, IL-12B, and GATA6 were found to be hypomethylated in endometriotic tissue by several studies. In regards to histone modification, multiple studies reported that the acetylation levels of histones H3 and H4 affect multiple genes associated with endometriosis. In addition, HDAC2 was found to be elevated in endometriosis patients in two studies. Conclusion: Several studies reported a significant difference between specific genes' methylation levels in endometrial biopsies and normal tissue, which suggests that DNA methylation may play an important role in the modulation of the genotype in endometriotic tissue. Acetylation and methylation are the two key histone modifications leading to differential gene expression in endometriotic tissues. The alterations in gene expression reported by the 57 studies can have direct implications on cell cycle growth, cell cycle arrest, and apoptosis and, therefore, might play a key role in the pathogenesis of endometriosis. This review offers insight that histone modifications need further research to evaluate their role as potential biomarkers and treatment targets for endometriosis. Although several key similarities were reported, there were some disagreements among the results, which might be attributable to the heterogeneity between studies. Further research with a more robust standardization is needed to validate the epigenetic changes in endometriosis.

Clinical utility of endoscopic ultrasound-guided tissue acquisition for comprehensive genomic profiling of patients with biliary tract cancer, especially with intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Endoscopic ultrasound-guided tissue acquisition (EUS-TA) is a standard diagnostic method for biliary tract cancer (BTC), and samples obtained in this manner may be used for comprehensive genomic profiling (CGP). This study evaluated the utility of EUS-TA for CGP in a clinical setting and determined the factors associated with the adequacy of CGP in patients with BTC. METHODS: CGP was attempted for 105 samples from 94 patients with BTC at the Aichi Cancer Center, Japan, from October 2019 to April 2022. RESULTS: Overall, 77.1% (81/105) of the samples were adequate for CGP. For 22-G or 19-G fine-needle biopsy (FNB), the sample adequacy was 85.7% (36/42), which was similar to that of surgical specimens (94%, p=0.45). Univariate analysis revealed that 22-G or larger FNB needle usage (86%, p=0.003), the target primary lesions (88%, p=0.015), a target size ≥30 mm (100%, p=0.0013), and number of punctures (90%, p=0.016) were significantly positively associated with CGP sample adequacy. CONCLUSIONS: EUS-TA is useful for CGP tissue sampling in patients with BTC. In particular, the use of 22-G or larger FNB needles may allow for specimen adequacy comparable to that of surgical specimens.

Genetic Profile of Rotavirus Type A in Children under 5 Years Old in Africa: A Systematic Review of Prevalence.

Human type A rotavirus (RV-A) is world-recognized as the major pathogen causing viral gastroenteritis in children under 5 years of age. The literature indicates a substantial increase in the diversity of rotavirus strains across continents, especially in Africa, which can pose significant challenges including an increase of disease burden and a reduction of vaccines' effectiveness. However, few studies have mapped the variety of circulating virus strains in different regions, which may hamper decisions on epidemiological surveillance and preventive public health measures. Thus, our aim was to compile the most updated available evidence on the genetic profile of RV-A among children in Africa and determine the prevalence of different genotypes according to the geographical regions by means of a broad systematic review. Systematic searches were performed in PubMed, Scopus, Web of Science, and Scielo without language, time limits, or geographical restrictions within the African continent. We selected full-text peer-reviewed articles assessing the genetic profile (i.e., genotyping) of RV-A in children up to 5 years old in Africa. Overall, 682 records were retrieved, resulting in 75 studies included for evidence synthesis. These studies were published between 1999 and 2022, were conducted in 28 countries from the five African regions, and 48% of the studies were carried out for 24 months or more. Most studies (n = 55; 73.3%) evaluated RV-A cases before the introduction of the vaccines, while around 20% of studies (n = 13) presented data after the vaccine approval in each country. Only seven (9.3%) studies compared evidence from both periods (pre- and post-vaccine introduction). Genotyping methods to assess RV-A varied between RT-PCR, nested or multiplex RT-PCR, testing only the most common P and G-types. We observed G1 and P[8] to be the most prevalent strains in Africa, with values around 31% and 43%, respectively. Yet if all the genotypes with the following highest prevalence were added ((G1 + G2, G3, G9) and (P[8] + P[6], P[4])), these figures would represent 80% and 99% of the total prevalence. The combination G1P[8] was the most reported in the studies (around 22%). This review study demonstrated an increased strain diversity in the past two decades, which could represent a challenge to the efficacy of the current vaccine.

Personalized Versus Precision Nanomedicine for Treatment of Ovarian Cancer.

The response to treatment is substantially varied between individual patients with ovarian cancer. However, chemotherapy treatment plans rarely pay sufficient attention to the mentioned factors. Instead, standardized treatment protocols are usually employed for most ovarian cancer patients. Variations in an individual's sensitivity to drugs significantly limit the effectiveness of treatment in some patients and lead to severe toxicities in others. In the present investigation, a nanotechnology-based approach for personalized treatment of ovarian carcinoma (the most lethal type of gynecological cancer) constructed on the individual genetic profile of the patient's tumor is developed and validated. The expression of predefined genes and proteins is analyzed for each patient sample. Finally, a mixture of the complex nanocarrier-based targeted delivery system containing drug(s)/siRNA(s)/targeted peptide is selected from the pre-synthesized bank and tested in vivo on murine cancer model using cancer cells isolated from tumors of each patient. Based on the results of the present study, an innovative approach and protocol for personalized treatment of ovarian cancer are suggested and evaluated. The results of the present study clearly show the advantages and perspectives of the proposed individual treatment approach.

Rapamycin as a Potential Alternative Drug for Squamous Cell Gingiva Carcinoma (Ca9-22): A Focus on Cell Cycle, Apoptosis and Autophagy Genetic Profile.

Oral cancer is considered as one of the most common malignancies worldwide. Its conventional treatment primarily involves surgery with or without postoperative adjuvant therapy. The targeting of signaling pathways implicated in tumorigenesis is becoming increasingly prevalent in the development of new anticancer drug candidates. Based on our recently published data, Rapamycin, an inhibitor of the mTOR pathway, exhibits selective antitumor activity in oral cancer by inhibiting cell proliferation and inducing cancer cell apoptosis, autophagy, and cellular stress. In the present study, our focus is on elucidating the genetic determinants of Rapamycin's action and the interaction networks accountable for tumorigenesis suppression. To achieve this, gingival carcinoma cell lines (Ca9-22) were exposed to Rapamycin at IC50 (10 µM) for 24 h. Subsequently, we investigated the genetic profiles related to the cell cycle, apoptosis, and autophagy, as well as gene-gene interactions, using QPCR arrays and the Gene MANIA website. Overall, our results showed that Rapamycin at 10 µM significantly inhibits the growth of Ca9-22 cells after 24 h of treatment by around 50% by suppression of key modulators in the G2/M transition, namely, Survivin and CDK5RAP1. The combination of Rapamycin with Cisplatin potentializes the inhibition of Ca9-22 cell proliferation. A P1/Annexin-V assay was performed to evaluate the effect of Rapamycin on cell apoptosis. The results obtained confirm our previous findings in which Rapamycin at 10 µM induces a strong apoptosis of Ca9-22 cells. The live cells decreased, and the late apoptotic cells increased when the cells were treated by Rapamycin. To identify the genes responsible for cell apoptosis induced by Rapamycin, we performed the RT2 Profiler PCR Arrays for 84 apoptotic genes. The blocked cells were believed to be directed towards cell death, confirmed by the downregulation of apoptosis inhibitors involved in both the extrinsic and intrinsic pathways, including BIRC5, BNIP3, CD40LG, DAPK1, LTA, TNFRSF21 and TP73. The observed effects of Rapamycin on tumor suppression are likely to involve the autophagy process, evidenced by the inhibition of autophagy modulators (TGFß1, RGS19 and AKT1), autophagosome biogenesis components (AMBRA1, ATG9B and TMEM74) and autophagy byproducts (APP). Identifying gene-gene interaction (GGI) networks provided a comprehensive view of the drug's mechanism and connected the studied tumorigenesis processes to potential functional interactions of various kinds (physical interaction, co-expression, genetic interactions etc.). In conclusion, Rapamycin shows promise as a clinical agent for managing Ca9-22 gingiva carcinoma cells.

Morphologic, phenotypic, and genotypic similarities between primary tumors and corresponding 3D cell cultures grown in a repeatable system-preliminary results.

BACKGROUND: Three-dimensional (3D) cell cultures are the new frontier for reproducing the tumor micro-environment in vitro. The aims of the study were (1) to establish primary 3D cell cultures from canine spontaneous neoplasms and (2) to demonstrate the morphological, phenotypic and genotypic similarities between the primary canine neoplasms and the corresponding 3D cultures, through the expression of tumor differentiation markers. RESULTS: Seven primary tumors were collected, including 4 carcinomas and 3 soft tissue sarcomas. 3D cell cultures reproduced the morphological features of the primary tumors and showed an overlapping immunophenotype of the primary epithelial tumors. Immunohistochemistry demonstrated the growth of stromal cells and macrophages admixed with the neoplastic epithelial component, reproducing the tumor microenvironment. Mesenchymal 3D cultures reproduced the immunophenotype of the primary tumor completely in 2 out of 3 examined cases while a discordant expression was documented for a single marker in one case. No single nucleotide variants or small indel were detected in TP53 or MDM2 genes, both in primary tumors and in 3D cell cultures specimens. In one sample, MDM2 amplicons were preferentially increased in number compared to TP53 ones, indicating amplification of MDM2, detectable both in the primary tumor and in the corresponding cell culture specimen. CONCLUSION: Here we demonstrate a good cell morphology, phenotype and genetic profile overlap between primary tumors and the corresponding 3D cultures grown in a repeatable system.

Advances in diffuse glial tumors diagnosis / Avanços no diagnóstico dos gliomas difusos

Abstract In recent decades, there have been significant advances in the diagnosis of diffuse gliomas, driven by the integration of novel technologies. These advancements have deepened our understanding of tumor oncogenesis, enabling a more refined stratification of the biological behavior of these neoplasms. This progress culminated in the fifth edition of the WHO classification of central nervous system (CNS) tumors in 2021. This comprehensive review article aims to elucidate these advances within a multidisciplinary framework, contextualized within the backdrop of the new classification. This article will explore morphologic pathology and molecular/genetics techniques (immunohistochemistry, genetic sequencing, and methylation profiling), which are pivotal in diagnosis, besides the correlation of structural neuroimaging radiophenotypes to pathology and genetics. It briefly reviews the usefulness of tractography and functional neuroimaging in surgical planning. Additionally, the article addresses the value of other functional imaging techniques such as perfusion MRI, spectroscopy, and nuclear medicine in distinguishing tumor progression from treatment-related changes. Furthermore, it discusses the advantages of evolving diagnostic techniques in classifying these tumors, as well as their limitations in terms of availability and utilization. Moreover, the expanding domains of data processing, artificial intelligence, radiomics, and radiogenomics hold great promise and may soon exert a substantial influence on glioma diagnosis. These innovative technologies have the potential to revolutionize our approach to these tumors. Ultimately, this review underscores the fundamental importance of multidisciplinary collaboration in employing recent diagnostic advancements, thereby hoping to translate them into improved quality of life and extended survival for glioma patients.

Resumo Nas últimas décadas, houve avanços significativos no diagnóstico de gliomas difusos, impulsionados pela integração de novas tecnologias. Esses avanços aprofundaram nossa compreensão da oncogênese tumoral, permitindo uma estratificação mais refinada do comportamento biológico dessas neoplasias. Esse progresso culminou na quinta edição da classificação da OMS de tumores do sistema nervoso central (SNC) em 2021. Esta revisão abrangente tem como objetivo elucidar esses avanços de forma multidisciplinar, no contexto da nova classificação. Este artigo irá explorar a patologia morfológica e as técnicas moleculares/genéticas (imuno-histoquímica, sequenciamento genético e perfil de metilação), que são fundamentais no diagnóstico, além da correlação dos radiofenótipos da neuroimagem estrutural com a patologia e a genética. Aborda sucintamente a utilidade da tractografia e da neuroimagem funcional no planejamento cirúrgico. Destacaremos o valor de outras técnicas de imagem funcional, como ressonância magnética de perfusão, espectroscopia e medicina nuclear, na distinção entre a progressão do tumor e as alterações relacionadas ao tratamento. Discutiremos as vantagens das diferentes técnicas de diagnóstico na classificação desses tumores, bem como suas limitações em termos de disponibilidade e utilização. Além disso, os crescentes avanços no processamento de dados, inteligência artificial, radiômica e radiogenômica têm grande potencial e podem em breve exercer uma influência substancial no diagnóstico de gliomas. Essas tecnologias inovadoras têm o potencial de revolucionar nossa abordagem a esses tumores. Em última análise, esta revisão destaca a importância fundamental da colaboração multidisciplinar na utilização dos recentes avanços diagnósticos, com a esperança de traduzi-los em uma melhor qualidade de vida e uma maior sobrevida.

Higher Prevalence of Nonsense Pathogenic DMD Variants in a Single-Center Cohort from Brazil: A Genetic Profile Study That May Guide the Choice of Disease-Modifying Treatments.

Dystrophinopathies are muscle diseases caused by pathogenic variants in DMD, the largest gene described in humans, representing a spectrum of diseases ranging from asymptomatic creatine phosphokinase elevation to severe Duchenne muscular dystrophy (DMD). Several therapeutic strategies are currently in use or under development, each targeting different pathogenic variants. However, little is known about the genetic profiles of northeast Brazilian patients with dystrophinopathies. We describe the spectrum of pathogenic DMD variants in a single center in northeast Brazil. This is an observational, cross-sectional study carried out through molecular-genetic analysis of male patients diagnosed with dystrophinopathies using Multiplex Ligation-dependent Probe Amplification (MLPA) followed by Next-Generation Sequencing (NGS)-based strategies. A total of 94 male patients were evaluated. Deletions (43.6%) and duplications (10.6%) were the most recurring patterns of pathogenic variants. However, small variants were present in 47.1% of patients, most of them nonsense variants (27.6%). This is the largest South American single-center case series of dystrophinopathies to date. We found a higher frequency of treatment-amenable nonsense single-nucleotide variants than most previous studies. These findings may have implications for diagnostic strategies in less-known populations, as a higher frequency of nonsense variants may mean a higher possibility of treating patients with disease-modifying drugs.

GPX3 Variant Genotype Affects the Risk of Developing Severe Forms of COVID-19.

In SARS-CoV-2 infection, excessive activation of the immune system intensively increases reactive oxygen species levels, causing harmful hyperinflammatory and oxidative state cumulative effects which may contribute to COVID-19 severity. Therefore, we assumed that antioxidant genetic profile, independently and complemented with laboratory markers, modulates COVID-19 severity. The study included 265 COVID-19 patients. Polymorphism of GSTM1, GSTT1, Nrf2 rs6721961, GSTM3 rs1332018, GPX3 rs8177412, GSTP1 rs1695, GSTO1 rs4925, GSTO2 rs156697, SOD2 rs4880 and GPX1 rs1050450 genes was determined with appropriate PCR-based methods. Inflammation (interleukin-6, CRP, fibrinogen, ferritin) and organ damage (urea, creatinine, transaminases and LDH) markers, complete blood count and coagulation status (d-dimer, fibrinogen) were measured. We found significant association for COVID-19 progression for patients with lymphocytes below 1.0 × 109/L (OR = 2.97, p = 0.002). Increased IL-6 and CRP were also associated with disease progression (OR = 8.52, p = 0.001, and OR = 10.97, p < 0.001, respectively), as well as elevated plasma AST and LDH (OR = 2.25, p = 0.021, and OR = 4.76, p < 0.001, respectively). Of all the examined polymorphisms, we found significant association with the risk of developing severe forms of COVID-19 for GPX3 rs8177412 variant genotype (OR = 2.42, p = 0.032). This finding could be of particular importance in the future, complementing other diagnostic tools for prediction of COVID-19 disease course.

Distinguished biological adaptation architecture aggravated population differentiation of Tibeto-Burman-speaking people.

Tibeto-Burman (TB) people have endeavored to adapt to the hypoxic, cold, and high-UV high-altitude environments in the Tibetan Plateau and complex disease exposures in lowland rainforests since the late Paleolithic period. However, the full landscape of genetic history and biological adaptation of geographically diverse TB-speaking people, as well as their interaction mechanism, remain unknown. Here, we generate a whole-genome meta-database of 500 individuals from 39 TB-speaking populations and present a comprehensive landscape of genetic diversity, admixture history, and differentiated adaptative features of geographically different TB-speaking people. We identify genetic differentiation related to geography and language among TB-speaking people, consistent with their differentiated admixture process with incoming or indigenous ancestral source populations. A robust genetic connection between the Tibetan-Yi corridor and the ancient Yellow River people supports their Northern China origin hypothesis. We finally report substructure-related differentiated biological adaptative signatures between highland Tibetans and Loloish speakers. Adaptative signatures associated with the physical pigmentation (EDAR and SLC24A5) and metabolism (ALDH9A1) are identified in Loloish people, which differed from the high-altitude adaptative genetic architecture in Tibetan. TB-related genomic resources provide new insights into the genetic basis of biological adaptation and better reference for the anthropologically informed sampling design in biomedical and genomic cohort research.